Pharmaceutical Research

, Volume 25, Issue 11, pp 2628–2638 | Cite as

Including Information on the Therapeutic Window in Bioequivalence Acceptance

  • Tom Jacobs
  • Filip De Ridder
  • Sarah Rusch
  • Achiel Van Peer
  • Geert Molenberghs
  • Luc Bijnens
Research Paper



A novel bioequivalence limit is proposed taking into account the therapeutic window.


The therapeutic range is introduced as the ratios maximum tolerated dose/therapeutic dose (MTD/D) and the therapeutic dose/lowest effective dose. The performance of the new acceptance range was compared with the methods of Schuirmann and Karalis. The method was retrospectively applied to data of three drugs with a narrow therapeutic window (phenytoin, theophylline and digoxin).


Simulations and examples show that the resulting bioequivalence limits are (1) narrow for narrow-index drugs, (2) expanded for highly variable drugs with a wide therapeutic window and (3) similar to the classical limits for less variable drugs with a wide therapeutic range.


The approach has the desirable property of resulting in a more narrow acceptance range for doses near the boundaries of the therapeutic window and a wider acceptance range for products with a broad therapeutic window.


average bioequivalence bioavailability individual bioequivalence therapeutic window 



Financial support from the IAP Research Network P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged.


  1. 1.
    S. Anderson, and W. Hauck. Consideration of individual bioequivalence. J. Pharmacokinet. Biopharm. 18(3):259–273 (1990). doi: 10.1007/BF01062202.PubMedCrossRefGoogle Scholar
  2. 2.
    F. Bochner, D. Huffman, D. Shen, and D. Azarnoff. Bioavailability of digoxin-hydroquinone complex: A new oral digoxin formulation. J. Pharm. Sci. 66(5):644–647 (1977). doi: 10.1002/jps.2600660510.PubMedCrossRefGoogle Scholar
  3. 3.
    A. Boddy, F. Snikeris, R. Kringle, G. Wei, J. Opperman, and K. Midha. An approach for widening the bioequivalence limits in the case of highly variable drugs. Pharm. Res. 12:1865–1868 (1995). doi: 10.1023/A:1016219317744.PubMedCrossRefGoogle Scholar
  4. 4.
    Committee for Proprietary Medicinal Products (CPMP), the European Agency for the Evaluation of Medicinal Products (EMEA). Note for guidance on the investigation of bioavailability and bioequivalence. (2001).Google Scholar
  5. 5.
    Committee for Proprietary Medicinal Products (CPMP), the European Agency for the Evaluation of Medicinal Products (EMEA). Concept paper for an addendum to the note for guidance on the investigation of bioavailability and bioequivalence: evaluation of bioequivalence of highly variable drugs and drug products. (2006).Google Scholar
  6. 6.
    U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products- General Considerations. (2003).Google Scholar
  7. 7.
    M. Gibaldi, and D. Perrier. Pharmacokinetics. New York, Marcel Dekker, (1982).Google Scholar
  8. 8.
    F. Hsuan. Some statistical considerations on the FDA draft guidance for individual bioequivalence. Stat. Med. 19:2879–2884 (2000). doi: 10.1002/1097-0258(20001030)19:202879::AID-SIM552>3.0.CO;2-9.PubMedCrossRefGoogle Scholar
  9. 9.
    V. Karalis, M. Symillides, and P. Macheras. Novel scaled average bioequivalence limits based on GMR and variability considerations. Pharm. Res. 21(10):1933–1942 (2004). doi: 10.1023/ Scholar
  10. 10.
    V. Karalis, P. Macheras, and M. Symillides. Geometric mean ratio-dependent scaled bioequivalence limits with leveling-off properties. Eur. J. Pharm. Sci. 26(1):54–61 (2005). doi: 10.1016/j.ejps.2005.04.019.PubMedCrossRefGoogle Scholar
  11. 11.
    P. Macheras, and A. Rosen. The bioequivalence factor. Pharm. Acta Helvetiae. 58(8):233–236 (1983).Google Scholar
  12. 12.
    M. C. Meyer, A. B. Straughn, R. M. Mhatre et al. Variability in the bioavailability of phenytoin capsules in males and females. Pharm. Res. 18:394–397 (2001). doi: 10.1023/A:1011075502215.PubMedCrossRefGoogle Scholar
  13. 13.
    Ministry of Health, Canada. Bioequivalence requirements: critical dose drugs. Ministry of Health, Canada, 2006.Google Scholar
  14. 14.
    G. Mistry, A. Laurent, A. Sterrett, and P. Deutsch. Effect of indinavir on the single-dose pharmacokinetics of theophylline in healthy subjects. J. Clin. Pharmacol. 39:636–642 (1999). doi: 10.1177/00912709922008146.PubMedCrossRefGoogle Scholar
  15. 15.
    D. Martin, D. Tompson, S. Boike, D. Tenero, B. Ilson, D. Citerone, and D. Jorkasky. Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers. Br. J. Clin. Pharmacol. 43:661–664 (1997). doi: 10.1046/j.1365-2125.1997.00608.x.PubMedCrossRefGoogle Scholar
  16. 16.
    J. O’Quigley, M. Pepe, and L. Fisher. Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics. 46:33–48 (1990). doi: 10.2307/2531628.PubMedCrossRefGoogle Scholar
  17. 17.
    S. Patterson, S. Francis, M. Ireson, D. Webber, and J. Whitehead. A novel Bayesian decision procedure for early-phase dose finding studies. J. Biopharm. Stat. 9:583–597 (1999). doi: 10.1081/BIP-100101197.PubMedCrossRefGoogle Scholar
  18. 18.
    J. Pinheiro, and D. Bates. Mixed-effects models in S and S-PLUS. Springer, Berlin, 2000.Google Scholar
  19. 19.
    D. Santos Buelga, M. J. Garcia, M. J. Otero, A. Martin Suarez, A. Dominguez-Gil, and J. C. Lukas. Phenytoin covariate models for Michaelis–Menten pharmacokinetics in adult epileptic patients. Page meeting, Paris, (2002).Google Scholar
  20. 20.
    L. B. Sheiner. Bioequivalence revisited. Stat. Med. 11:1777–1788 (1992). doi: 10.1002/sim.4780111311.PubMedCrossRefGoogle Scholar
  21. 21.
    D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the average bioavailability. J. Pharmacokinet. Biopharm. 15:657–680 (1987). doi: 10.1007/BF01068419.PubMedCrossRefGoogle Scholar
  22. 22.
    V. Steinijans, R. Sauter, D. Hauschke, E. Diletti, R. Schall, H. Luus, M. Elze, H. Blume, C. Hoffmann, G. Franke, and W. Siegmund. Reference tables for the intrasubject coefficient of variation in bioequivalence studies. Int. J. Clin. Pharmacol. Ther. 33:427–430 (1995).PubMedGoogle Scholar
  23. 23.
    J. Wagner. Fundamentals of clinical pharmacokinetics. Drug Intelligence, Hamilton, 1975.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Tom Jacobs
    • 1
  • Filip De Ridder
    • 2
  • Sarah Rusch
    • 2
  • Achiel Van Peer
    • 2
  • Geert Molenberghs
    • 1
    • 3
  • Luc Bijnens
    • 2
  1. 1.Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Universiteit Hasselt, and Katholieke Universiteit Leuven, BelgiumDiepenbeekBelgium
  2. 2.Johnson and Johnson Pharmaceutical Research and Development, A Division of Janssen PharmaceuticaBeerseBelgium
  3. 3.Katholieke Universiteit Leuven, International Institute for Biostatistics and Statistical BioinformaticsLeuvenBelgium

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